Abstract Currently, clinically used drug abuse medications exist for treatment of addiction to opiates, alcohol, and nicotine, but not cocaine. The objective of the proposed project is to test the hypothesis that the partial kappa agonist PPL-103 can be effective as a pharmacotherapy for treatment of cocaine abuse. Because of chronic drug-induced changes in the kappa opioid receptor system, kappa receptor-directed compounds have been proposed as potential drug abuse medications. The kappa receptor antagonist JDTic has been shown to be effective in some models of cocaine abuse and a brief clinical trial was initiated. Another approach would be to use a kappa partial agonist, which would be expected to diminish the dysphoric properties of the upregulated dynorphin system. Nalmefene, a kappa partial agonist that is approved for alcohol abuse in Europe, accomplishes this, however mu antagonism in this compound can be aversive in itself. Phoenix PharmaLabs (PPL) has developed a novel family of opioid receptor ligands, including PPL-103, which displays a unique combination of high binding affinity and novel activities at the three opioid receptors (kappa, mu, and delta). It is a potent, moderate efficacy kappa agonist, it is potent but has very low efficacy as mu agonist, and it is a moderate efficacy delta agonist. PPL-103 is not dysphoric like most kappa agonists, but is also not self-administered in rats. Despite low mu efficacy, it does not precipitate withdrawal, and even substitutes for morphine in morphine-dependent animals. In addition, PPL-103 exerts minimal effects on motor coordination and gastrointestinal transit in animals. Therefore, we hypothesize that this compound offers substantial potential as a superior cocaine addiction therapy. Therefore, the aim of the project is to test that hypothesis using the cocaine self-administration assay in rats. Specific Aim 1 will determine whether systemically administered PPL-103 (0, 0.3, 1, 3 mg/kg, i.p.) can attenuate cocaine self-administration in both short access (ShA, 1h) and long access (LgA, 6h) self-administration sessions in both male and female rats. Specific Aim 2 will determine whether PPL-103 blocks relapse of cocaine self-administration using the reinstatement paradigm. In these experiments PPL-103 will be tested for its ability to block reinstatement induced by the three primary mediators of relapse, a cocaine prime, drug associated cues, and stress, as induced by the chemical stressor yohimbine. These straightforward experiments will determine whether a kappa partial agonist can effectively attenuate cocaine taking and seeking behavior and whether PPL-103 has appropriate characteristics to act as a potential cocaine abuse pharmacotherapy.